saralasin and Acute-Disease

Acute pancreatitis is an inflammatory disease characterized by pancreatic tissue edema, acinar cell necrosis, hemorrhage and inflammation of the damaged gland. It is believed that acinar cell injury is initiated by the activation of digestive zymogens inside the acinar cells, leading finally to the autodigestion of the pancreas. Previous study in our laboratory demonstrated that cerulein-induced acute pancreatitis was associated with an up-regulation of local renin-angiotensin system (RAS) in rat pancreas. Therefore, the utilization of RAS inhibitors may provide a novel and alternative treatment for acute pancreatitis. By means of a rat model of cerulein-induced acute pancreatitis, results from the present study showed that an intravenous injection of saralasin, an antagonist for angiotensin II receptors, at a dose of 40 microg/kg 30 min before the induction of acute pancreatitis significantly attenuated pancreatic edema. Results from the biochemical measurements showed that pretreatment with saralasin at a dose of 20 microg/kg markedly reduced pancreatic injury, as evidenced by the decreased activities of alpha-amylase and lipase in plasma. However, the same recipe of ramiprilat, a specific inhibitor for angiotensin-converting enzyme, at a dose of 20 microg/kg did not provide any protective effect against acute pancreatitis. On the contrary, pretreatment with ramiprilat at a dose 40 microg/kg enhanced cerulein-induced pancreatic injury. Results from histopathological analysis of these RAS inhibitors further confirmed with those results as obtained from biochemical analysis. These data indicate that administration of saralasin but not ramiprilat could be protective against acute pancreatitis and that activation of pancreatic RAS in acute pancreatitis may play a role in pancreatic tissue injury.

Topics: Acute Disease; alpha-Amylases; Angiotensin Receptor Antagonists; Animals; Ceruletide; Disease Models, Animal; Edema; Injections, Intravenous; Lipase; Necrosis; Pancreatitis; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Saralasin

Free radical-mediated pancreatic injury is believed to play a key role in the pathogenesis of acute pancreatitis. Most of these studies have focused on the effects of antioxidant enzymes and free radical scavengers on improving the pancreatic injury. Recent findings showed that cerulein-induced acute pancreatitis was associated with an upregulation of a local pancreatic renin-angiotensin system in the pancreas. In the current study we hypothesized that inhibition of this renin-angiotensin system by saralasin, a nonspecific antagonist for angiotensin II receptor, could attenuate the severity of cerulein-induced pancreatitis.. The effects of saralasin on oxidative stress and tissue injury in cerulein-induced pancreatitis were assessed by histopathologic analysis and on the basis of biochemical changes of plasma alpha-amylase level, pancreatic glutathione status, oxidative modification of protein, and lipid peroxidation.. Data from the biochemical analysis showed that intravenous injections of saralasin at doses of 10 microg/kg to 50 microg/kg 30 minutes before the induction of acute pancreatitis significantly reduced pancreatic injury, as indicated by a decrease in plasma alpha-amylase activity in comparison with the cerulein-treated control. The effect of saralasin was further manifested by significant suppressions of glutathione depletion, oxidative modification of proteins, and lipid peroxidation in cerulein-treated rat pancreas. Histopathologic examination findings were in agreement with the biochemical data.. These data suggest that prophylactic administration of saralasin can ameliorate the oxidative stress and tissue injury in cerulein-induced pancreatitis. Such a protective effect may provide new insight into the potential value of angiotensin II receptor antagonists in the clinical therapy for acute pancreatitis.

Topics: Acute Disease; alpha-Amylases; Angiotensin Receptor Antagonists; Animals; Ceruletide; Glutathione; Lipid Peroxidation; Oxidative Stress; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Saralasin

Intravenous infusion of arginine vasopressin (AVP) depresses the slope of the ventilatory response to CO2 during acute hypercapnia. We therefore tested the hypothesis that AVP V1-receptor blockade would increase the slope of the ventilatory response to CO2. After a 20-min control period, an AVP V1-receptor antagonist (d(CH2)5[Tyr(Me)2]AVP) was injected into six conscious resting dogs. Thirty minutes after AVP V1-receptor blockade, dogs were exposed to sequential 20-min periods of 5 and 6.5% inspired CO2 in air. A second protocol (no AVP V1-receptor blockade) was conducted as a control. As predicted, AVP V1-receptor blockade enhanced ventilation during inhalation of 6.5% CO2 in association with an increased metabolic rate and increased plasma angiotensin II (ANG II). In eupneic dogs, stimulation of respiration by AVP V1-receptor blockade is mediated by ANG II. A third protocol with ANG II-receptor blockade (intravenous infusion of saralasin) combined with AVP V1-receptor blockade indicated that ANG II mediated the increase in metabolism and the augmented ventilation during inhalation of 6.5% CO2. We conclude that during acute hypercapnia of sufficient magnitude, and perhaps duration, AVP inhibits an ANG II-mediated stimulation of metabolism and respiration.

Topics: Acid-Base Equilibrium; Acute Disease; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Dogs; Fluid Shifts; Hemodynamics; Hypercapnia; Infusions, Intravenous; Male; Renin; Respiration; Saralasin

The present study was designed to investigate the effect of a lack of vasopressin resulting from electrolytic lesion of the median eminence of the hypothalamus on the acute 45-min aortic coarctation hypertension elicited in conscious rats by means of a pneumatic cuff placed around the aorta above the renal arteries. Forty-eight hours after lesion, aortic constriction elicited a prompt (5-min) rise in mean carotid pressure from 115 +/- 2 to 149 +/- 2 mmHg, followed by a gradual decline to 129 +/- 2 mmHg. In contrast, sham-lesioned rats exhibited a prompt hypertensive response from 118 +/- 2 to 157 +/- 2 mmHg that leveled off throughout the experiment. Lesioned rats treated with saralasin presented a blunted hypertensive response (within 125 +/- 2 to 130 +/- 2 mmHg), whereas sham-lesioned rats showed only a delay in the onset of hypertension. The hypertensive response of lesioned rats was unaffected by the vasopressin antagonist [d(CH2)5Tyr(Me)]AVP, whereas sham-lesioned rats submitted to this treatment presented a prompt rise in pressure followed by a gradual decline at the end of the experiment. Lesioned and sham-lesioned rats treated with saralasin plus vasopressin antagonist showed a blunted hypertensive response throughout the experiment. These data demonstrate that the integrity of the median eminence plays a pivotal role in the maintenance (30-45 min) of acute aortic coarctation hypertension, presumably involving the release of vasopressin from the neurohypophysis, whereas angiotensin II mainly accounts for the prompt (5-15 min) rise in pressure.

Topics: Acute Disease; Animals; Aortic Coarctation; Arginine Vasopressin; Blood Pressure; Hypertension; Male; Median Eminence; Rats; Rats, Wistar; Saralasin; Vasopressins

We reported that intravenous infusion of angiotensin II (ANG II) stimulated ventilation (VE) in conscious dogs. Other studies in our laboratory have demonstrated that increases in respiration occurred in association with activation of the renin-angiotensin system during acute hypotension and during hypercapnia. Therefore, in conscious dogs (n = 5), we examined the effects of ANG II receptor blockade with intravenous saralasin (0.5 micrograms.kg-1.min-1) on respiratory responses during progressive nitroprusside-induced hypotension and during the ventilatory response to increased inspired fraction of CO2 (VRC). During hypotension (mean arterial pressure decreased approximately 20%) combined with ANG II receptor blockade, VE, heart rate, and arginine vasopressin increases were attenuated compared within unblocked studies. With ANG II receptor blockade during hypotension, alveolar ventilation and arterial PCO2 (PaCO2) were unchanged, which contrasted with a doubling of alveolar ventilation and a decrease of 4.8 +/- 1 Torr in PaCO2 in unblocked studies. During hypercapnia, the slope of the VRC was not affected by ANG II receptor blockade, but with 6.5% inspired CO2 fraction, VE and PaCO2 were lower than in unblocked studies. These results indicated that ANG II contributed to the respiratory response to a modest hypotension but did not affect respiratory sensitivity to CO2.

Topics: Acute Disease; Angiotensin II; Animals; Arginine Vasopressin; Blood Glucose; Blood Pressure; Dogs; Hypercapnia; Hypotension; Male; Nitroprusside; Osmolar Concentration; Oxygen Consumption; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Respiration; Saralasin

To evaluate our previous observation of renal vasoconstriction during combined acute hypoxemia and hypercapnic acidosis preceded by acute hypoxemia, we studied 13 conscious mongrel uninephrectomized dogs with chronic renal catheters and controlled sodium intake (80 meq/day for 4 days). Five dogs were studied during combined acute hypoxemia (PaO2, 37 +/- 1 mm Hg) and hypercapnic acidosis (PaCO2, 59 +/- 1 mm Hg; pH 7.20 +/- 0.01). Each dog was studied during infusion of 1) the intrarenal vehicle (n = 5), 2) the intrarenal alpha 1-antagonist prazosin (0.2 micrograms.kg-1.min-1, n = 5), 3) intrarenal [Sar1,Ala8]angiotensin II (70 ng.kg-1.min-1, n = 5), and 4) intrarenal prazosin and [Sar1,Ala8]angiotensin II (n = 4). Immediate induction of combined hypoxemia and hypercapnic acidosis after control measurements during intrarenal vehicle infusion resulted in a decrease in effective renal plasma flow and glomerular filtration rate, increase in renal vascular resistance, and decrease in filtered sodium load in the first 20 minutes of the blood gas derangement. Intrarenal administration of [Sar1,Ala8]angiotensin II failed to reverse the effects of the combined blood gas derangement on renal function. In contrast, intrarenal prazosin administration either alone or in combination with [Sar1,Ala8]angiotensin II abrogated the increase in renal vascular resistance, decrease in glomerular filtration rate, and fall in filtered sodium load. These studies identify a major role for alpha 1-adrenoceptors in the renal vasoconstriction during combined hypoxemia and hypercapnic acidosis.

Topics: Acidosis; Acute Disease; Adrenergic alpha-Antagonists; Angiotensin II; Animals; Dogs; Hypercapnia; Hypoxia; Kidney; Pharmaceutical Vehicles; Phenylephrine; Prazosin; Receptors, Adrenergic, alpha; Renal Circulation; Saralasin; Vasoconstriction

The role of vasopressin (AVP) and angiotensin II (ANG II) in the onset of acute (45 min) aortic coarctation hypertension was studied in conscious rats. Changes in mean carotid pressure (MCP) and heart rate (HR) were measured in four groups of rats. Control rats presented a hypertensive response that attained a plateau 5 min after coarctation and remained near this level throughout the experiment. Rats treated with AVP V1-vascular receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-(O-methyl)tyrosine]arginine vasopressin [d(CH2)5Tyr(Me)AVP] presented a prompt rise in MCP similar to the control rats, but in contrast to this group, the MCP started to decline progressively. Rats treated with saralasin presented a delay in the onset of hypertension right after coarctation but slowly attained values similar to those for control rats. In contrast, the rats treated with AVP antagonist plus saralasin showed a blunted MCP elevation throughout the experiment. Reflex bradycardia observed in the rats treated with saralasin or the AVP antagonist plus saralasin was similar to that observed in the control rats, whereas for the group treated only with AVP antagonist, the reflex bradycardia was more intense than for the other three groups, indicating an increased sensitivity of the baroreflex. These data demonstrate that in addition to the mechanical effect of aortic constriction, both ANG II and AVP participate in the onset of acute aortic coarctation hypertension. Moreover, the results indicate that ANG II acts on the prompt (5 min) rise in pressure, whereas AVP is responsible for the maintenance (30-45 min) of the arterial pressure elevation.

Topics: Acute Disease; Angiotensin II; Animals; Aortic Coarctation; Arginine Vasopressin; Blood Pressure; Carotid Arteries; Heart Rate; Hypertension; Male; Rats; Rats, Inbred Strains; Saralasin; Vasopressins

Intrarenal administration of angiotensin I converting enzyme (ACE) inhibitors carried out in norepinephrine- (NE; 2-4 micrograms/kg per min) or in angiotensin II- (ANG II; 60-90 ng/kg per min) induced acute hypertension in conscious unrestrained rabbits. Intrarenal administration of captopril (5 mg/kg) and MK-422 (1 mg/kg) caused no significant effect when injected intravenously. However, it showed a prompt and marked depressor effect in NE- but not in ANG II-induced hypertension. This effect was not observed after intrarenal infusion of saralasin (2 and 10 micrograms/kg per min) in NE-induced hypertension. While pretreatment with aprotinin or indomethacin failed to inhibit the depressor action, 2-bromoethylamine hydrobromide (BEA), which is known to induce necrosis of the renal papilla, produced complete abolition of the depressor effect of an intrarenal injection of MK-422 in NE-induced hypertension. These results indicate that the kidney plays an important role in the depressor action of ACE inhibitors in NE- but not in ANG II-induced acute hypertension, and that this effect may be related to the potentiation of antihypertensive renomedullary lipids rather than the inhibition of the renin-angiotensin system or the potentiation of bradykinin or prostaglandins.

Topics: Acute Disease; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Female; Heart Rate; Hypertension; Indomethacin; Kidney; Norepinephrine; Rabbits; Saralasin

We investigated the antagonistic properties of saralasin in acute and chronic angiotension II (ANG II)-dependent hypertension. Two models of experimental hypertension were studied: (a) Rats acutely infused i.v. with ANG II to raise the blood pressure (BP) by about 35 mmHg. (b) One-clip, two-kidney renal hypertensive rats. In both experimental models increasing doses of saralasin were infused i.v., and three parameters were evaluated at each dose level: (1) fall of BP, (2) plasma concentration of saralasin, and (3) plasma concentration of ANG II. It was found that saralasin led to a more pronounced fall of BP in malignant than in benign renal hypertension. To reduce BP by about 20 mmHg, saralasin plasma concentrations had to exceed those of ANG II about 2000-fold in renal hypertension and about 7-fold in rats infused with ANG II. It is concluded that saralasin antagonises ANG II more effectively in acute than in chronic hypertension.

Topics: Acute Disease; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Chronic Disease; Hypertension, Malignant; Hypertension, Renovascular; Male; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Saralasin

Topics: Acute Disease; Angiotensin II; Animals; Chronic Disease; Hypertension, Renal; Male; Rats; Renin; Saralasin

Intrarenal infusion of Sar1-Ala8 angiotensin II(P113), a competitive antagonist of angiotensin II, failed to reverse or prevent the decreased ipsilateral renal blood flow and increased renal resistance characteristic of chronic unilateral ureteral occlusion and did not significantly alter plasma renin activity in the chronic state. Thus, angiotensin II does not appear to play a significant role in the hemodynamic response to unilateral ureteral occlusion.

Topics: Acute Disease; Angiotensin II; Animals; Chronic Disease; Dogs; Female; Glomerular Filtration Rate; Kidney; Regional Blood Flow; Renin; Saralasin; Ureteral Obstruction; Vascular Resistance